tbuckley/cabot-search huggingface dataset:
Impact of race on treatment outcomes in triple-negative breast cancer at an academic medical center.
Authors: Jasmine Patterson, Jane Lowe Meisel, Sha Yi, Yuan Liu, Yichun Cao, Xiaoxian Li
Journal: Journal of Clinical Oncology (2022)

e12616 Background: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and in all but the smallest tumors, neoadjuvant chemotherapy (NACT) is part of the standard of care. Black women (BW) suffer a poorer prognosis than white women (WW) with TNBC, and whether this is due to differences in treatment, disease biology, or socioeconomic variables is not fully known. This study, conducted at a racially diverse academic medical center, aimed to investigate factors associated with unfavorable outcomes in BW with TNBC. Methods: 131 patients with TNBC received NACT from 2008-2017 at Winship Cancer Institute were included in this retrospective study. Descriptive statistics were applied to delineate the relationship with racial disparity. Clinical outcomes include progression free survival (PFS) and distance metastasis free survival (DMFS) and were analysis using Cox proportional hazard model. Results: Among 131 patients with TNBC treated with NACT, 58.5% were BW and median age was 55. BW and WW had similar disease staging at diagnosis and similar pathologic responses to treatment. Yet, BW were less likely to complete NACT compared with WW (80.8% BW completed NACT vs 98.0% WW, p=0.005). BW were more likely to either not complete NACT or to require dose reduction or dose delay (42.5% BW vs. 23.1% WW, p=0.024). Coexisting hypertension (65.8% BW vs. 35.2% WW), elevated BMI (31.7% BW vs. 27.5% WW), or covered by Medicaid (29.3% BW vs. 13.0% WW) were more common among BW. Medicaid insurance was associated with worse progression-free survival (HR 2.49, p=0.015) and distant metastasis free survival (DMFS, HR 2.73, p=0.018). Dose delays were associated with worse DMFS (HR 3.02, p=0.017). Discussion: In this study, we found that BW were less likely to complete NACT than WW, more likely to suffer dose delays, and more likely to require dose reductions. BW were also more likely to have Medicaid insurance, another factor that correlated with inferior outcomes; perhaps because patients with Medicaid insurance are also more likely to suffer from reduced access to transportation, childcare, and other infrastructure critical to maintaining a schedule for NACT. More research is needed to understand the reasons for the dose delays, dose reductions, and failures to complete NACT so that interventions can be designed to address them. Conclusions: As we move into the era of chemoimmunotherapy for TNBC, where drug combinations and treatment schedules are becoming even more complex, a better understanding of the reasons for dose delays, dose reductions, and treatment discontinuations will be key to maintaining optimal outcomes for TNBC patients, regardless of race.
Association of parental cancer and minor child’s unmet economic needs in food, housing, and transportation.
Authors: Zhiyuan Zheng, Ahmedin Jemal, Jingxuan Zhao, Xuesong Han, Qinjin Fan, K. Robin Yabroff
Journal: Journal of Clinical Oncology (2022)

12014 Background: A cancer diagnosis is associated with substantial economic burden among cancer survivors and their families. Some families make sacrifices that adversely affect food, housing, and transportation to offset high out-of-pocket medical expenses. Cancer survivors with minor children may be particularly vulnerable to financial hardship, even years after diagnosis. However, little is known about the extent to which parental cancer affects minor children’s food insecurity, unmet housing needs, and delayed medical care due to transportation barriers. Methods: The 2013 to 2018 National Health Interview Survey was used to identify minor children (ages 5-17 years) living in families with a parental cancer history (n = 812, representing 860,488 children) and children without a parental cancer history (n = 22,129, representing about 24.5 million children). Multivariable logistic regressions were used to compare family-level food insecurity, parent’s worry about ability to pay monthly bills and housing costs, and delayed medical care for the child because of no transportation between minor children with and without a parental cancer history. All analyses adjusted for child-, parent-, and family-related characteristics, including child’s age group, sex, and race/ethnicity; parent’s age group, sex, race/ethnicity, health insurance coverage, number of comorbid conditions, and obesity status; family’s structure (married/cohabiting parents versus single parent families), highest educational attainment in the family, and family income as a percentage of the federal poverty level. Results: About 3.4% of minor children were living in families with a parental cancer history. In adjusted analyses and compared to children whose parents did not report a history of cancer, children of cancer survivors were more likely to live in families that experience shortages in basic economic needs, such as food bought did not last 26.0% (95% confidence intervals[CI]: 22.3%-29.7%) vs 16.7% (95CI: 16.1%-17.3%), inability to afford balanced meals 16.9% (95CI: 13.8%-20.0%) vs 13.3% (95CI: 12.8%-13.8%), worry about paying monthly bills 44.8% (95CI: 40.6%-48.9%) vs 37.9% (95CI: 37.1%-38.7%), and worry about housing costs 35.7% (95CI: 31.9%-39.5%) vs 30.7% (95CI: 30.0%-31.5%). Moreover, children with a parental cancer history were more likely to experience delayed medical care due to lack of transportation than children without a parental cancer history 3.6% (95CI: 2.2%-4.9%) vs 1.6% (95CI: 1.4%-1.9%), all p &lt;.05. Conclusions: Parental cancer is associated with greater likelihood of food insecurity, worse housing and other living conditions, and transportation barriers to medical care for minor children. Efforts to identify minor children with a parental cancer history and develop strategies to attenuate their unmet economic needs are warranted.
SARS-CoV-2 Omicron variants BA.1 and BA.2 both show similarly reduced disease severity of COVID-19 compared to Delta, Germany, 2021 to 2022
Authors: Claudia Sievers, Benedikt Zacher, Alexander Ullrich, Matthew Huska, Stephan Fuchs, Silke Buda, Walter Haas, Michaela Diercke, Matthias an der Heiden, Stefan Kröger
Journal: Eurosurveillance (2022)

German national surveillance data analysis shows that hospitalisation odds associated with Omicron lineage BA.1 or BA.2 infections are up to 80% lower than with Delta infection, primarily in ≥ 35-year-olds. Hospitalised vaccinated Omicron cases’ proportions (2.3% for both lineages) seemed lower than those of the unvaccinated (4.4% for both lineages). Independent of vaccination status, the hospitalisation frequency among cases with Delta seemed nearly threefold higher (8.3%) than with Omicron (3.0% for both lineages), suggesting that Omicron inherently causes less severe disease.
MEDB-16. Persistent radiological lesions at the end of primary therapy in childhood medulloblastoma: residual lesion or active residual tumor?
Authors: Lena Schömig, Denise Obrecht, Martin Mynarek, Brigitte Bison, Rudolf Schwarz, Torsten Pietsch, Stefan Rutkowski, Martin Benesch
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Magnetic resonance imaging (MRI) of patients with medulloblastoma (MB) often shows persistent residual findings after primary treatment. Criteria for characterizing these lesions and consensus on further therapeutic approaches are not established. MATERIAL AND METHODS: Eighty-four patients ≥4 years with centrally reviewed residual lesions on MRI at the end of primary therapy with initial surgery between 2000 and 2018 were identified. Data were extracted from the German HIT-MED database. RESULTS: Median age at initial diagnosis was 9.3 (4.0-20.8) years. 91.7% were histologically classified as CMB, 7.1% as LC/AMB and 1.2% as DMB. The majority (65.5%) of the evaluated cohort was assigned to molecular subgroup 4, 24.1% to group 3, 6.8% to WNT, 3.4% to SHH. Median follow-up for survivors was 5.96 (1.41-16.67) years. Univariate analysis revealed that patients showing an overall partial response (PR) to primary therapy have a significantly lower risk of progression of residual lesions compared to patients with stable disease (SD) (5-year PFS [PR]: 62.5±7,0; 5-year PFS [SD]: 35.9±12.8; 5-year OS [PR]: 85.6±5.1; 5-year OS [SD]: 54.1±13.7; p=0.02 [PFS], p=0.04 [OS]). Additionally, patients with multiple residual lesions (M+ and R+) were at higher risk of progression (5-year PFS [R+ only]: 72.4±12.0, 5-year PFS [R+/M+]: 22.9±17.9; p=0.02 [PFS]). Further procedures after the end of primary therapy (additional resections, chemotherapy, radiotherapy) did not impact on PFS and OS. These results were confirmed by multivariate Cox regression. For molecular or histological type no significant effect was found, presumably due to small cohort. CONCLUSION: PFS in patients with residual lesions at the end of primary treatment depends on the overall response to primary therapy. Additional procedures do not seem to be superior compared to watch-and-wait strategies. Decisions regarding further therapies should be scrutinized on a case-by-case basis. Further identification of biomarkers is warranted.
T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma
Authors: Xuefeng Wang, Jameel Muzaffar, Kedar Kirtane, Feifei Song, Matthew Johnson, Michael J Schell, Jiannong Li, Sean J Yoder, Jose R Conejo-Garcia, Jose A Guevara-Patino, Marcelo Bonomi, Priyanka Bhateja, James W Rocco, Conor E Steuer, Nabil F Saba, Christine H Chung
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background T cell receptor (TCR) signaling profile is a fundamental property that underpins both adaptive and innate immunity in the host. Despite its potential clinical relevance, the TCR repertoire in peripheral blood has not been thoroughly explored for its value as an immunotherapy efficacy biomarker in head and neck squamous cell carcinoma (HNSCC). The purpose of the present study is to characterize and compare the TCR repertoire in peripheral blood mononuclear cells (PBMC) from patients with HNSCC treated with the combination of cetuximab and nivolumab. Methods We used the immunoSEQ assay to sequence the TCR beta (TCR-B) chain repertoire from serially obtained PBMC at baseline and during the treatments from a total of 41 patients who received the combination ( NCT03370276 ). Key TCR repertoire metrics, including diversity and clonality, were calculated and compared between patients with different therapy responses and clinical characteristics (eg, human papillomavirus (HPV) status and smoking history). Patient survival outcomes were compared according to patient groups stratified by the TCR-B clonotyping. To confirm the observed patterns in TCR spectrum, samples from patients who achieved complete response (CR) and partial response (PR) were further profiled with the immunoSEQ deep resolution assay. Results Our data indicated that the patients who achieved CR and PR had an increased TCR sequence diversity in their baseline samples, this tendency being more pronounced in HPV-negative patients or those with a smoking history. Notably, the CR/PR group had the lowest proportion of patients with oligoclonal TCR clones (2 out of 8 patients), followed by the stable disease group (9 out of 20 patients) and lastly the progressive disease group (7 out of 10 patients). An overall trend toward favorable patient survival was also observed in the polyclonal group. Finally, we reported the shared TCR clones across patients within the same response group, as well as the shared clones by aligning immunoSEQ reads with TCR data retrieved from The Cancer Genome Atlas- head and neck squamous cell carcinoma (TCGA-HNSC) cohort. Conclusions Our data suggest that, despite the great clinical heterogeneity of HNSCC and the limited responders in the present cohort, the peripheral TCR repertoires from pretreatment PBMC may be developed as biomarkers for the benefit of immunotherapy in HNSCC.
PATH-14. Alteration of histopathological diagnoses by molecular profiling
Authors: Stephanie Knirsch, Till Milde, Stefan M Pfister, Claudia Blattmann
Journal: Neuro-Oncology (2022)

Abstract Here, we present a 4.5 year old patient presented with disturbed vision (double vision) and nausea over 2 weeks. Cerebral MRI revealed a tumor mass (6.5 x 6 x 5cm) located in the left temporal lobe. A macroscopical complete resection was achieved in May 2020. Conventional histopathology diagnosed a glioblastoma multiforme WHO IV° locally as well upon central review. A pleomorphic xanthoastrocytoma was considered to be unlikley due to the lack of eosinophile granular corpuscules, CD34-positive cells and dense reticulin fibres. The patient received treatment according to the SIOP HGG protocol with a postsurgical radiotherapy (total dosage of 54 Gy) accompanied by oral chemotherapy with temozolomide and valproic acid. After completion of radiotherapy, another 12 cycles of oral temozolomide were applied resulting in 1 year of consolidation treatment. In parallel, the tumor tissue was examined molecularly through the INFORM precision oncology platform (INdividualized Therapy FOr Relapsed Malignancies in Childhood). The results revealed an NTRK1-fusion as possible treatment target. Furthermore, methylation profiling of the tumor classified it as a pleomorphic xanthoastocytoma. The molecular results were completed during treatment of the patient and were discussed interdisciplinary. Finally, the diagnosis was changed integrating histopathology and molecular results, but the treatment was completed. In about 10% of the brain tumor cases within molecular diagnostic studies such as INFORM or PTT, the histopathological diagnosis differs from the molecular results leading to reconsideration of the initial diagnosis and potential impact on clinical management. These results demonstrate the importance of molecular profiling in brain tumors (and sarcomas) to complement conventional histopathology and select appropriate risk adapted treatment, especially in young patients.
Pharmacokinetic and pharmacodynamic analysis of adavosertib in advanced ovarian cancer.
Authors: Amit M. Oza, Stephanie Lheureux, Ainhoa Madariaga, Mihaela C. Cristea, Gina Mantia-Smaldone, Alexander Olawaiye, Susan Ellard, Johanne I Weberpals, Andrea Elisabeth Wahner Hendrickson, Gini F. Fleming, Stephen Welch, Neesha C. Dhani, Vanessa Speers, Valerie Bowering, Lisa Wang, Wenjiang Zhang, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2022)

5579 Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m 2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.
RONC-01. A 10 year, single institution experience of re-irradiation for paediatric intracranial tumours
Authors: Kimberley Durno, Pei Lim, Vanita Gandhi, Ananth Shankar, Christine Dahl, Mette Jorgensen, Mark Gaze, Jenny Gains, Yen-Ch'ing Chang
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Re-irradiation has become integral in the management of relapsed and recurrent intracranial tumours in children. It is used as salvage therapy for a number of tumours including; diffuse intrinsic pontine glioma (DIPG), high grade glioma (HGG), ependymoma and medulloblastoma. We report the patient demographics, dose, outcomes and toxicity for patients treated with re-irradiation at our institute. METHODS: 33 patients with a diagnosis of DIPG (n=11, 33%), ependymoma (n=11, 33%), HGG (n=4, 12%) or medulloblastoma/sPNET (n=7, 21%), treated with intracranial re-irradiation since 2012 were analysed in this retrospective study. Statistical survival analysis was performed. RESULTS: The median follow-up was 19 months (range 0–216 months). The median age at re-irradiation was 10 years (2-20 years). The median time from first radiation to re-radiation was 34 months (range 3–113 months). Re-irradiation techniques included; photons (n=26), protons (n=2) and stereotactic radiotherapy (n=6). The median re-irradiation dose was 36.37Gy EQD2 (range 20-95.05Gy), given in dose per fraction between 1.8Gy–2Gy. The median overall survival (OS) and progression free survival (PFS) for the cohort was 15.68 months and 7 months respectively. For DIPG, the median OS and PFS were 6.12 months and 4 months respectively. At 2 years, the OS and PFS rates for the cohort were 34.37% and 32.45% respectively. For the non-DIPG cohort, the 2 year OS and PFS rates were 55.37% and 48.13% respectively. In the DIPG cohort, 88% (n=7) had a reported symptomatic benefit from re-irradiation. A stable or improved radiological response was reported in majority of patients (78%, n=18). No acute or late toxicities ≥ grade 3 were reported within the cohort, specifically, there were no reports of brainstem necrosis. CONCLUSION: Re-irradiation for paediatric intracranial tumours is safe and offers a benefit to patients. Further work is ongoing to evaluate cumulative brainstem doses and predictive variables.
Gepotidacin is efficacious in a nonhuman primate model of pneumonic plague
Authors: Charles Jakielaszek, Mohammad Hossain, Lian Qian, Cindy Fishman, Katherine Widdowson, Jamese J. Hilliard, Frank Mannino, Aparna Raychaudhuri, Elisabeth Carniel, Samandra Demons, Henry S. Heine, Jeremy Hershfield, Riccardo Russo, William M. Mega, David Revelli, Karen O’Dwyer
Journal: Science Translational Medicine (2022)

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode and has the potential to treat a number of bacterial diseases. Development of this new agent to treat pneumonic plague caused by Yersinia pestis depends on the U.S. Food and Drug Administration Animal Rule testing pathway, as testing in humans is not feasible. Here, preclinical studies were conducted in the African green monkey (AGM) inhalational model of pneumonic plague to test the efficacy of gepotidacin. AGMs infected with Y. pestis were dosed intravenously with gepotidacin (48, 36, or 28 milligrams/kilogram per day) for 10 days to provide a plasma concentration that would support a rationale for a 1000 mg twice or thrice daily intravenous dose in humans or saline as a control. The primary end point was AGM survival with predefined euthanasia criteria. Secondary end points included survival duration and bacterial clearance. Gepotidacin showed activity in vitro against diverse Y. pestis isolates including antibiotic-resistant strains. All control animals in the inhalational plague studies succumbed to plague and were blood culture and organ culture positive for Y. pestis . Gepotidacin provided a 75 to 100% survival benefit with all dose regimens. All surviving animals were blood culture and organ culture negative for Y. pestis . Our randomized, controlled efficacy trials in the AGM pneumonic plague nonhuman primate model together with the in vitro Y. pestis susceptibility data support the use of gepotidacin as a treatment for pneumonic plague caused by Y. pestis .
Harnessing allogeneic NK cells: improving outcomes with tailored donor lymphocyte infusion
Authors: Shannon R. McCurdy
Journal: Journal of Clinical Investigation (2022)

Since researchers first began to uncover the mechanisms underlying allogeneic transplantation, the focus has been on T cells. T cells are a major instigator of graft-versus-host disease (GVHD). The clear association between GVHD occurrence and subsequent reduction in relapse supported concentrating on T cells as the masterminds behind graft-versus-tumor (GVT) effects. Recently, an alternative mediator of GVT has taken center stage: natural killer (NK) cells. Part of the appeal of NK cells is their potential to provide antitumor immunity without GVHD. Donor lymphocyte infusion has been the predominant treatment of relapse after allogeneic transplant, but the mix of lymphocytes includes CD8+ T cells and, consequently, a substantial risk for GVHD. In this issue of the JCI, Shapiro and colleagues developed an adoptive NK cell transfer platform to treat relapse after haploidentical allogeneic transplant. The study demonstrated safety, sought to determine resistance mechanisms, and provided avenues for future research.